1. Field of the Invention
The invention relates to compositions and methods for suppressing the immune system of a mammal using ubiquitin and derivatives and analogs thereof.
2. Background Information
Ubiquitin, a small (8.6 kDa), heat stable and highly conserved 76 amino acid protein in all eukaryotic cells was originally identified as an immunopoetic polypeptide from thymocytes [1,2]. Further research has suggested that ubiquitin plays a key role in essential intracellular functions such as cell differentiation, cell cycle control, heat shock response, and regulation of immune responses [3–5]. Traditionally, the most important function of ubiquitin was considered to be regulation of protein turnover by the ubiquitin-proteasome-pathway [3–6]. There is no known physiologic function for extracellular ubiquitin, even though it is normally present in the extracellular space. Significantly increased ubiquitin levels above normal have been described in serum or plasma during parasitic infections [7], in alcoholic liver cirrhosis [8], type 2 diabetes [9], hairy cell leukemia [10], and in patients with renal failure and hemodialysis treatment [11,12]. In various in vitro conditions, extracellular ubiquitin can alter lymphocyte differentiation, inhibit IgG production in splenocyte cultures, and regulate growth and amyloid formation in hematopoietic cells [1,10,13,14,16]. In a murine macrophage cell line (RAW 264.7), ubiquitin potentiates endotoxin (LPS) induced TNF production [15]. Otherwise, the function of extracellular ubiquitin is unknown.
The present application discloses a new biological function of extracellular ubiquitin and demonstrates that 1) exogenous ubiquitin acts as a cytokine-like protein with anti-inflammatory properties and 2) administration of exogenous ubiquitin prevents sequelae of a harmful activation of the immune system in vivo.